VO is a vicious cycle. Formation of sickle cells is the first step in VO. Thereafter, sickle cells interact with leukocytes, endothelial cells, and platelets to form an occlusive clot. Downstream of the occlusion, hypoxia then causes the formation of more sickle cells. Once the clot is broken up, ischemia-reperfusion produces oxidative injury, which further activates cells and promotes VO. Thus begins a cycle of adhesion, inflammation, and VO, wherein more sickle cells are generated and the process of VO is amplified with each turn of the cycle. Selectins and invariant NKT (iNKT) cells are 2 critical elements of the VO cycle. (Top) P-selectin binds sickle cells and leukocytes, representing the first step of adhesion. In a later step of adhesion, E-selectin binds leukocytes and may induce activation signals to promote the capture the sickle red cells. The end result of P-selectin and E-selectin actions is an occlusive clot. (Bottom) Ischemia-reperfusion, after clot break up, activates iNKT cells, which produce numerous cytokines, including interferon gamma (IFNγ), interleukin 4 (IL-4), and tumor necrosis factor alpha (TNFα). The iNKT cell-generated cytokines activate and attract leukocytes, and may activate the endothelium to express selectins. TNFα, in particular, promotes the up-regulation of E-selectin.